PROJECT SUMMARY Cardiometabolic diseases including coronary artery disease (CAD) and type 2 diabetes (T2D) are major causes of death and morbidity in all societies. These and other metabolic diseases have common etiological insults, including dyslipidemia, the pathological elevation of triglyceride-rich lipoproteins (TRLs) and low-density lipoprotein cholesterol (LDL-C), and treating these risk factors has been shown to reduce disease burden and progression. While statins effectively lower LDL-C, many people are intolerant to their adverse effects and these drugs may not address the residual vascular risk conferred by other proatherogenic lipoproteins such as TRLs, including very low density lipoproteins (VLDLs). VLDLs are precursors to LDL that are synthesized and secreted from the liver to provide triglycerides to peripheral tissues, and thus one underexplored potential avenue for reducing TRL-mediated dyslipidemia is to curb hepatic VLDL secretion. The regulation of VLDL secretion is complex and incompletely understood. Apolipoprotein B (apoB), the key protein component of VLDL, is synthesized in the hepatocyte under tight post-transcriptional control by multiple regulatory pathways, and secreted from the hepatocyte into the circulation to provide nutrition in the form of triglycerides to peripheral tissues. The precise coordination of the pathways governing the fate of apoB as matures into secreted VLDL particles, especially in post-endoplasmic reticulum compartments, is poorly known. A novel gene arising from genome-wide association studies (GWAS) for plasma lipid traits is the SORT1 gene, encoding sortilin, a ubiquitously expressed multi-ligand sorting receptor. Our laboratory previously established SORT1 as the causal gene at the genomic locus associated with plasma cholesterol and CAD and demonstrated that sortilin negatively regulates VLDL-apoB secretion. However, the detailed molecular mechanisms underlying sortilin?s regulation of apoB metabolism and VLDL secretion remain unknown. The precise understanding of how sortilin regulates lipoprotein metabolism and cardiometabolic risk may have important therapeutic implications. The goal of this fellowship proposal is thus to fully elucidate the mechanisms and coordination of VLDL-apoB metabolism by sortilin in the liver and the heart. Specifically, Dr. Conlon will investigate the hypothesis that hepatic sortilin regulates the post-ER fate of apoB for degradation and export to combat lipid overload and secretory stress and that sortilin functions to coordinate intracellular apoB metabolism in response to the number and quality of apoB particles that reach the Golgi and the level of post-ER pre-secretory proteolysis (PERPP) activity. To test this hypothesis, Sort1 liver specific knockout mice and in vitro hepatocyte models will be utilized in the presence of various stressors. Additionally, she will explore how apoB secretion might protect cardiomyocytes from lipotoxicity and the role of sortilin in regulating cardiac apoB secretion. This proposal also aims train Dr. Conlon in new techniques and provide mentoring to allow her to transition into an independent investigator with a career in academics.